Journal
GASTROENTEROLOGY
Volume 132, Issue 3, Pages 1117-1126Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2007.01.053
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Funding
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI023598] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS052471] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [R01AA011975, R56AA011975, R01AA013868] Funding Source: NIH RePORTER
- NIAAA NIH HHS [AA11975, R56 AA011975, AA013868, R01 AA011975, R01 AA013868] Funding Source: Medline
- NIAID NIH HHS [AI23598, R01 AI023598] Funding Source: Medline
- NINDS NIH HHS [R01 NS052471, R01 NS052471-04] Funding Source: Medline
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Background & Aims: The complement pathway is an important component of the innate and adaptive immune response. Here we tested the hypothesis that activation of complement is required for development of ethanol-induced fatty liver. Methods: Wild-type mice and mice lacking the third (C3) or fifth (C5) components of the complement activation pathway, as well as mice lacking decay-accelerating factor (CD55/DAF), a complement regulatory protein, were fed Lieber-DeCarli ethanol-containing diets for 6 weeks or pair-fed control diets. Results: Ethanol feeding to wild-type mice increased C3a in plasma. Wild-type and C5(-/-) mice fed the ethanol diet developed hepatic steatosis characterized by microvesicular and macrovesicular lipid accumulation and increased triglyceride content. C3(-/-) mice did not develop steatosis, while CD55/DAF(-/-) mice accumulated even more hepatic triglyceride after ethanol feeding than wild-type mice. Levels of serum alanine aminotransferase and hepatic tumor necrosis factor a, indicators of hepatocyte injury and inflammation, respectively, were increased in wild-type and CD55/DAF(-/-) mice but not in C5(-/-) mice after ethanol feeding. In contrast to the protective effect of C3(-/-) against ethanol-induced steatosis, levels of both alanine aminotransferase and tumor necrosis factor a were increased in C3(-/-) mice after ethanol feeding Conclusions: Here we have identified several elements of the complement system as important contributors to ethanol-induced fatty liver. C3 contributed primarily to the accumulation of triglyceride in the liver, whereas C5 was involved in inflammation and injury to hepatocytes. Further, the absence of CD55/DAF exacerbated these responses, suggesting that CD55/DAF serves as a barrier to ethanol-induced fatty liver.
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